Clinical and outcome comparison of genetically positive vs. negative patients in a large cohort of suspected familial hypocalciuric hypercalcemia

Abstract

Objective: Biochemical suspicion of familial hypocalciuric hypercalcemia (FHH) might provide with a negative (FHH-negative) or positive (FHH-positive) genetic result. Understanding the differences between both groups may refine the identification of those with a positive genetic evaluation, aid management decisions and prospective surveillance. We aimed to compare FHH-positive and FHH-negative patients, and to identify predictive variables for FHH-positive cases.

Design: Retrospective, national multi-centre study of patients with suspected FHH and genetic testing of the CASR, AP2S1 and GNA11 genes.

Methods: Clinical, biochemical, radiological and treatment data were collected. We established a prediction model for the identification of FHH-positive cases by logistic regression analysis and area under the ROC curve (AUROC) was estimated.

Results: We included 66 index cases, of which 30 (45.5%) had a pathogenic variant. FHH-positive cases were younger (p = 0.029), reported more frequently a positive family history (p < 0.001), presented higher magnesium (p < 0.001) and lower parathormone levels (p < 0.001) and were less often treated for hypercalcemia (p = 0.017) in comparison to FHH-negative cases. Magnesium levels showed the highest AUROC (0.825, 95%CI: 0.709-0.941). The multivariate analysis revealed that family history and magnesium levels were independent predictors of a positive genetic result. The predictive model showed an AUROC of 0.909 (95%CI: 0.826-0.991).

Conclusions: The combination of magnesium and a positive family history offered a good diagnostic accuracy to predict a positive genetic result. Therefore, the inclusion of magnesium measurement in the routine evaluation of patients with suspected FHH might provide insight into the identification of a positive genetic result of any of the CaSR-related genes.

Keywords: CASR gene; CASR mutations; Familial hypocalciuric hypercalcemia (FHH); calcium disorders; calcium-sensing receptor (CaSR); primary hyperparathyroidism (PHPT).

Fig. 1

Serum Mg²⁺ levels. A Serum Mg²⁺ levels according to FHH-genotype. Serum Mg²⁺ levels are lower in the FHH-negative than in the FHH-positive group (p < 0.001). B Discriminative accuracy of serum Mg²⁺ levels for classifying patients as FHH-negative or FHH-positive. The area under the ROC curve was 0.825 (95% CI: 0.709–0.941)

Fig. 2

The area under the ROC curve of the model for the discrimination between FHH-positive and FHH-negative participants was 0.909 (95%CI: 0.826–0.991). Footnote: the model included the following variables: family history, serum Mg²⁺ levels, PTH levels and age